Over the past decade, the use of MRI to study multiple sclerosis (MS) has lead to substantial advances in understanding the disease process. Disease activity as detected by new lesions on T2-weighted images or contrast enhancing lesions on T1-weighted images have established that the level of activity seen on MRI is considerably greater than that seen clinically. Further, MRI has become an important and powerful tool for the assessment of the effect of new experimental therapies in MS. Recent work continues to focus on defining the natural history of the disease using MRI and in examining the effect of experimental treatments on disease activity as measured by MRI. Specifically, recent studies have focused on the following questions; 1. What is the natural history of new lesions in MS identified by contrast enhancement? Components of this question include a comparison of disease activity using contrast enhancement, lesion load on T2-weighted images and advanced imaging techniques including magnetization transfer imaging and proton spectroscopy. 2. What is the level of disease activity seen in patients who are early in the relapsing remitting course of the disease? 3. Interferon beta 1b is approved for the treatment of MS and has been shown to produce over the short term a reduction in disease activity as measured by MRI. Does the treatment effect persist and what, if any, effect does the development of neutralizing antibodies have on the efficacy of the treatment? 4. What effect do treatments that are chosen to target various aspects of the MS lesion have on disease activity and which MRI measures are best for studying treatments that target the various stages of the lesion? Serial studies of patients with early,relapsing-remitting MS using contrast enhanced MRI have shown that nearly two thirds of the patients have evidence of active new lesion formation. Recent studies in the NIB have examined the evolution of the MS lesion using imaging techniques that measure tissue destruction such as lesion load on T2-weighted images or T1 hypointensities, alterations in magnetization transfer ratios and alterations seen using proton spectroscopy. Findings have demonstrated that progression of disease as measured by overall burden of disease increases during the early phase of the disease. However, only a modest correlation can be found between the frequency of acute enhancing lesions and the level of accumulated disease burden suggesting that distinct mechanisms may contribute to lesion progression. In a cohort of 35 patients treated with interferon beta 1b and studied longitudinally by MRI, clinical evaluation and interferon neutralizing antibody status, development of neutralizing antibodies was found in 12 patient (34%). In almost all cases some change in the treatment effect of interferon on acute contrast enhancing lesion activity was observed corresponding to the development of neutralizing antibodies. However, 6 of the patients had a spontaneous reduction or disappearance of neutralizing antibody; these patients continued to have a substantial reduction in disease activity as measured by contrast enhancing activity. Thus, while a relationship seems to exist between the effect of the treatment and the presence of neutralizing antibody, the use of single antibody determinations have limited usefulness. Studies of the effect of experimental treatments on various stages of the MS lesion can provide valuable information at several levels. In addition to providing evidence that a treatment may be effective in the disease, changes in the evolution of the MS lesion on MRI during the use of an experimental treatment can help establish the mechanism involved in the pathogenesis of the lesion. Consequently, recent studies in the NIB have focused on treatments that are thought to modify different aspects of lesion development. Studies have been started which examine the effect of a treatment designed to modify the T cell response to myelin basic protein and a treatment that may protect the oligodendrocyte from damage or stimulate some regeneration. Patients treated with interferon beta 1b have been studied using multiple MRI techniques in order to establish the stage of the MS lesion modified by this treatment. Evidence indicates that while interferon treatment is very effective in many patients in reducing the frequency of new inflammatory lesions, the treatment does not prevent the enlargement of existing lesions nor does it lead to any significant remyelination. These finding not only help in understanding the mechanism of interferon in MS but also indicate that the MS lesion may have multiple components and that these components are not necessarily a continuum but instead distinct process that can operate independently.